Method of treating inflammatory conditions with progesterone or progesterone analogs

ABSTRACT

The present invention provides methods for treating inflammatory conditions, including but not limited to, inflammatory bowel disease (ulcerative colitis, Crohn&#39;s disease, and proctitis), other noninfectious, inflammatory conditions of the GI tract (microscopic colitis, allergic eosinophilic gastroenteritis, food allergies, pill induced esophagitis, celiac disease, recurrent polyps, and hemorrhoids), and psoriasis, using progesterone or progesterone analogs such as medroxyprogesterone acetate.

PRIORITY INFORMATION

This application claims priority to U.S. Provisional Patent ApplicationNo. 60/156,434, filed Sep. 28, 1999.

TECHNICAL FIELD

This invention provides methods for treating inflammatory conditions,including but not limited to, inflammatory bowel disease (ulcerativecolitis, Crohn's disease, and proctitis), other noninfectious,inflammatory conditions of the GI tract (microscopic colitis, allergiceosinophilic gastroenteritis, food allergies, pill induced esophagitis,celiac disease, recurrent polyps, and hemorrhoids), and psoriasis usingprogesterone and progesterone analogs.

BACKGROUND OF THE INVENTION

Inflammatory Bowel Disease

“Inflammatory bowel disease” (IBD) encompasses the idiopathic, chronicinflammatory bowel diseases ulcerative colitis (UC), Crohn's disease(CD), and proctitis. Researchers do not know the cause of thesediseases, but believe that they involve genetic and immunologicinfluences on the gastrointestinal tract's ability to distinguishforeign from self-antigens and/or to alter the mucosal immune response.They share many overlapping epidemiological, clinical, and therapeuticfeatures. IBD affects up to 1,000,000 Americans and disease symptoms canbe so severe as to prevent the patient from carrying on a normal life.The total cost of the disease, including lost productivity, in the US istwo billion dollars per year. Ward et al., Clinical economics review:medical management of inflammatory bowel disease, Ailment Pharmacol Ther13:15-25 (1999). Drug therapies that allow patients to avoid surgicalintervention could reduce the cost significantly.

IBD (UC, CD, and proctitis) is different from spastic colon or irritablebowel syndrome, which is a motility disorder of the gastrointestinaltract. UC is characterized by a diffuse, continuous, superficial,ulcerative inflammation of the colon, not due to any known single cause.The inflammation often begins within the rectum and extends proximallyinto the bowel. UC affects the inner mucosal layer of the colon (laminapropria) in a continuous manner, with no portions of healthy tissuesbetween the diseased areas. Additionally, it affects only the colon, notother areas of the gastrointestinal (GI) tract, except in rareinstances. UC may be accompanied by bloody diarrhea, constipation, veryfrequent bowel movements (often 15 to 20 per day), explosive diarrhea,rectal incontinence, pus, mucus, gas, fever, tachycardia, weakness, andanemia. UC creates striking changes in the mucosa and submucosa of thecolon and rectum. The disease causes diffuse severe ulceration,inflammation, and congestion of the lining of the colon and rectum. Moresevere disease states include thinning of the bowel, susceptibility toulcers, fibrosis, contraction, and narrowing of the intestinal lumen.

CD is characterized by focal, asymmetric, transmural inflammationaffecting any portion of the gastrointestinal tract from the mouth tothe anus. The ileum and right colon are, however, most often involved.CD affects all layers of the intestine, but there can be patches ofnormal bowel in between the diseased regions. Depending on where in thebowel the disease manifests itself, CD can cause nausea, vomiting,epigastric pain, diarrhea, cramping abdominal pain, rectal bleeding,loss of appetite, fever, night sweats, malaise, arthralgias, and weightloss. Proctitis, inflammation of the rectum, is invariably present in UCand is sometimes present in CD. It may also occur independently fromthese diseases.

Proctitis is another manifestation of IBD with pathology similar to UC.A patient presenting with proctitis may later develop full-blown UC orCD.

Physicians and medical researchers have not been successful inidentifying a cause for these diseases, although several theories havebeen postulated. The diseases may be caused by a pathogen or otherantigen that initiates the inflammatory response in the bowel,accompanied by a defect in the ability to down-regulate the immuneresponse. Once initiated, many of the pathophysiological events in IBDare related to amplification of the inflammatory process. In response toantigens, cytokines and other inflammatory mediators are released. Somecytokines promote T cell activity. The inflammatory cascade continueswith IL-2, helper T cells, B-cell proliferation, and antibody synthesis.Stimulated neutrophils and macrophages accumulate and further damage thetissue by releasing reactive oxygen species and other biologicallyactive products. Additional acute inflammatory cells respond to thetissue damage, whether or not the primary initiating stimulus hasceased.

Other research on IBD suggests that abnormalities in the immune system,nonimmune cells in the intestinal mucosa, genetic risk determinants, andrandom environmental factors may all be necessary to induce IBD.Papadakis et al., Current Theories on the Causes of Inflammatory BowelDisease, Gastroenterol Clin North Am 28:283-296 (1999). Researchers havealso postulated that tumor necrosis factor-α (TNF-α), a proinflammatorycytokine, may play an important role in the pathogenesis of inflammatorybowel disease. Sanborn et al, Antitumor necrosis factor therapy forinflammatory bowel disease: a review of agents, pharmacology, clinicalresults, and safety, Inflamm Bowel Dis 5:119-33 (1999). The uncertaintyabout the cause of IBD has lead to confusion about the appropriatetreatment strategy.

Currently, no treatment exists that will cure or effectively manage bothforms of inflammatory bowel disease. Present treatments includeaminosalicylates (sulfasalazine, mesalamine), glucocorticoids(hydrocortisone, prednisone), antibiotics (to reduce secondaryinfection), immunosuppressants (6-mercaptopurine, cyclosporine),belladonna, atropine, and phenobarbital. Immunosuppressants(6-mercaptopurine, azathioprine, FK-506/tacrolimus) andneuroimmunomodulation agents (somatostatin, substance P, localanesthetics) have also been used as therapy for IBD. Prevention ofadhesion and recruitment has been suggested by using antisenseoligonucleotides to ICAM-1. Other miscellaneous therapies that have beensuggested include arachidonic acid metabolites, anti-free radicals,short-chain fatty acids, nicotine, bismuth, ketotifen, heparin,interferon-α, chloroquinone/hydroxychloroquine, hyperbaric oxygen, IVimmunoglobulin, and leukapheresis. Sands, Novel Therapies forInflammatory Bowel Disease, Inflammatory Bowel Disease 28:323-351(1999).

Infliximab, an anti-TNF-α antibody, has recently been developed as atreatment for Crohn's disease, because overproduction of TNF-α leads toinflammation. Biological activities attributed to TNF-a includeinduction of pro-inflammatory cytokines such as IL-1 and IL-6,enhancement of leukocyte migration by increasing endothelial layerpermeability and expression of adhesion molecules by endothelial cellsand leukocytes, and activation of neutrophil and eosinophil functionalactivity. REMICADE™ (Infliximab) Prescribing Information.

Additional medical management strategies include psychotherapy, dietcontrol, fluid and electrolytes. A significant number of patients mustresort to surgical removal of the affected portion of the bowel. None ofthe known therapies provide successful long term treatment for allpatients, and many of the therapies have serious side effects. Forexample, patients treated with steroid drugs, such as glucocorticoids,can develop diabetes, hypertension, psychological changes, Cushingssyndrome, changes in protein metabolism, osteoporosis, cataracts,avascular hip necrosis, and infection. Patients takingimmunosuppressants run serious risk of infection and may have anincreased incidence of cancer.

Other Noninfectious, Inflammatory Conditions of the GI Tract

Improved treatments are also needed for other noninfectious,inflammatory conditions of the GI tract, including but not limited tomicroscopic colitis, allergic eosinophilic gastroenteritis, foodallergies, pill induced esophagitis, celiac disease, recurrent polyps,and hemorrhoids.

Microscopic colitis is another form of colitis, where only microscopicchanges are seen in the GI tract tissue. No gross clinicalmanifestations are visible upon colonoscopy. Patients with microscopiccolitis commonly have diarrhea.

Allergic eosinophilic gastroenteritis can be diagnosed upon biopsy ofthe GI tract tissue, which will show predominantly eosinophilicinfiltration of the bowel wall. This inflammatory condition is inducedby an allergic reaction to food, microbes, or other ingested substancethat come in contact with the bowel wall. Cramping pain, diarrhea, andweight loss are common. This condition is often treated with prednisone.Food allergies can also cause other inflammatory conditions in the GItract, and are often treated with steroid hormones, such as theglucocorticoids.

Pill-induced esophagitis is an inflammatory condition of the esophaguscaused when a pill becomes lodged in the esophagus during swallowing.The inflammatory condition can continue even after the pill becomesdislodged.

Celiac disease is an inflammatory condition of the small intestine,precipitated by the ingestion of wheat, rye, and barley, in individualssensitive or allergic to these foods. While sensitive individuals cantry to avoid these foods, it is very difficult to prevent accidentalingestion, and patients very often require treatment. Symptoms of celiacdisease include diarrhea, bloating, and discomfort.

Recurrent polyps are also thought to have an inflammatory component,with inflammation in the colon and around the polyps. Polyps are aserious, precancerous GI condition, and are generally removedsurgically. A treatment is needed to prevent polyps from recurring ortreat them without surgical intervention.

Hemorrhoids, enlarged and inflamed veins in the wall of the anus, areusually a consequence of prolonged constipation or diarrhea. Theinflammatory process affects the veins and the tissues surrounding theveins. Hemorrhoids can occur with IBD (UC, CD, and proctitis) and mayalso occur independently of these diseases. This inflammatory conditionof the GI tract can be treated with anti-inflammatory steroid drugs,such as glucocorticoids, or surgery.

Psoriasis

Psoriasis, another inflammatory condition, affects more than 7 millionAmericans. It is a noncontaigious skin disorder that most commonlyappears as inflamed swollen skin lesions covered with silvery whitescale. The exact cause of psoriasis is not known, but a patient'skeratinocytes grow as if there was a wound, in a regenerative maturationprocess. The skin cannot shed the extra cells fast enough, and excessiveskin cells build up and form elevated, scaly lesions. Psoriasis occursin several forms including: plaque psoriasis, guttate psoriasis, inversepsoriasis, erythrodermic psoriasis, pustular psoriasis, psoriaticarthritis, scalp psoriasis, and nail psoriasis.

Various treatment strategies have been used for psoriasis, though noneare completely effective. Topical steroid medications are one of themost common therapies prescribed. Steroids can also be injected into thelesions. Topical retinioids have also been useful. Phototherapy offers asecond level of treatment for more persistent cases. The third level oftreatment includes systemic drugs such as methotrexate, oral retinoids,and cyclosporin.

Recent research has suggested that psoriasis may respond to treatmentwith an anti-TNF-α monoclonal antibody. Oh, C. J., et al., Treatmentwith anti-tumor necrosis factor alpha (TNF-α) monoclonal antibodydramatically decreases the clinical activity of psoriasis lesions, J.Am. Acad. Dermatol., 42:829-30 (2000). Elevated levels of TNF-α havebeen associated with psoriasis, especially psoriatic arthritis andpsoriasis vulgaris. Ritchlin C., et al., Patterns of cytokine productionin psoriatic synovium, J. Rheumatol., 25:1544-52 (1998); Okubo Y, etal., Peripheral blood monocytes in psoriatic patients overproducecytokines, J. Dermatol. Sci., 17:223-32 (1998).

Medroxyprogesterone Acetate

Medroxyprogesterone acetate is a derivative of progesterone and is awhite, odorless crystalline powder, stable in air, melting between 2000and 210° C. The chemical name for medroxyprogesterone acetate ispregn-4-ene-3,20-dione, 17-(acetyloxy)-6-methyl-, (6α)-. Its structuralformula is as follows:

Medroxyprogesterone acetate is currently prescribed for secondaryamenorrhea, abnormal uterine bleeding due to hormonal imbalance, andcontraception. Medroxyprogesterone acetate has also been combined withestrogens for treatment of menopausal symptoms. Medroxyprogesteroneacetate, acting through its regulation of the menstrual cycle, can alsobe used for reduced iron-deficiency anemia, protection against pelvicinflammatory disease, protection from endometrial cancer, and improvedhematologic parameters among users with sickle cell disease. Cullins,Noncontraceptive Benefits and Therapeutic Uses of DepotMedroxyprogesterone Acetate, Journal of Reproductive Medicine,41:428-433 (1996). Thus, it is surprising that the administration ofprogesterone or progesterone analogs is effective in the treatment ofinflammatory conditions, including but not limited to, inflammatorybowel disease (ulcerative colitis, Crohn's disease, and proctitis),other noninfectious, inflammatory conditions of the GI tract(microscopic colitis, allergic eosinophilic gastroenteritis, foodallergies, pill induced esophagitis, celiac disease, recurrent polyps,and hemorrhoids), and psoriasis.

SUMMARY OF THE INVENTION

It is an object of the present invention to provide a method fortreating a patient suffering from at least one of the followingconditions: inflammatory conditions, including but not limited to,inflammatory bowel disease (ulcerative colitis, Crohn's disease, andproctitis), other noninfectious, inflammatory conditions of the GI tract(microscopic colitis, allergic eosinophilic gastroenteritis, foodallergies, pill induced esophagitis, celiac disease, recurrent polyps,and hemorrhoids), and psoriasis wherein a progesterone or progesteroneanalog is administered to the patient.

It is an object of the present invention to provide a method fortreating a patient suffering from inflammatory conditions, including butnot limited to, inflammatory bowel disease (ulcerative colitis, Crohn'sdisease, and proctitis), other noninfectious, inflammatory conditions ofthe GI tract (microscopic colitis, allergic eosinophilicgastroenteritis, food allergies, pill induced esophagitis, celiacdisease, recurrent polyps, and hemorrhoids), and psoriasis, whereinmedroxyprogesterone acetate is administered to the patient.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to a method for treating a patientsuffering from at least one of the following inflammatory conditions,including but not limited to, inflammatory bowel disease (ulcerativecolitis, Crohn's disease, and proctitis), other noninfectious,inflammatory conditions of the GI tract (microscopic colitis, allergiceosinophilic gastroenteritis, food allergies, pill induced esophagitis,celiac disease, recurrent polyps, and hemorrhoids), and psoriasis,wherein progesterone or a progesterone analog is administered to thepatient.

Progesterone analogs for use in the invention include, but are notlimited to: acetophenone derivative of 16α, 17α-dihydroxyprogesterone,allyestrenol, chlormadinone acetate, cyproterone acetate, desogestrel,dimethisterone, dydrogesterone, esthisterone, estrenols,ethinylestrenol, ethlestrenol, ethynodiol diacetate, hydroxyprogesteronecaproate, medroxyprogesterone acetate, megestrol acetate,norethandrolone, norethindrone, norethindrone enanthate, norethisterone,norethynodrel, norgestimate, norgestrel, 19-nortestosterone, andvalerate and caproate esters of progesterone.

In one embodiment of the invention, the progesterone analog ismedroxyprogesterone acetate. Other embodiments includemedroxyprogesterone and its other salts and derivatives. While notwishing to be bound by any theory, it is believed that during IBD andother noninfectious, inflammatory conditions of the bowel, lymphocytesmay infiltrate the bowel, drawn there by a cytokine or other chemotacticor inflammatory mediators. Progesterone and progesterone analogs mayinhibit the release of the cytokine or other chemotactic agent from acell in the bowel, thus decreasing the number of lymphocytes that arerecruited to the bowel. Progesterone and progesterone analogsdownregulate the Fc receptors in macrophages. The Fc receptor recognizesantibodies or immune complexes present in an inflammatory process, andsuch stimulation of the Fc receptor is one of the ways that themacrophage is signaled to release TNF-α and IL-6.

Progesterone analogs with higher “classic progestational activity”, asdetermined by in vitro binding to the uterus or other uterine activity,can provide more effective treatment in the present invention. Thepresence and extent of classic progesterone activity are determined bythe effect of the compound on the uterus. For example, in the rabbit theextent of the effect on the uterine endometrium is determined. TereniusL., Affinities of progestogen and estrogen receptors in rabbit uterusfor synthetic progestogens, Steroids 23:909-919 (1974); Goth A., MedicalPharmacology, C. V. Mosby Co., St. Louis, p. 429 (1966); Duncan M R, etal., An in vivo study of the action of antiglucocorticoids on thymusweight ratio, antibody titre, and the adrenal pituitary hypothalamusaxis, J. Steroid Biochemistry 10:245-59 (1979). 17-hydroxyprogesteroneand analogs of progesterone that have less progestational classic sexhormone activity may be less effective in the present method. However,derivatives of 17-hydroxyprogesterone that have progestational activitywill be effective in the invention.

In one advantageous embodiment, the progesterone or progesterone analogwill have low bioavailability, so that much of it will remain in the GItract, in bowel disorders, or on the skin, for topical psoriasisdisorders, directly treating the diseased tissue. Lower bioavailabilitymay be advantageous because decreased systemic absorption could resultin decreased systemic side effects and complications. This could allowpatients with chronic conditions to receive treatment for longer periodsof time. Although not wishing to be bound by theory, it is believed thatthe invention may work through a combination of local and systemiceffects.

A selective delivery system should provide even more effectivetreatment. Such a selective delivery system could include an entericcoated tablet or capsule, a low solubility tablet, capsule, suspension,suppository, enema, liquid, foam, cream, gel, ointment, powder, or anyof the following forms discussed below. Enteric coatings can be appliedto tablets to gain local delivery to various portions of thegastrointestinal tract (for example, upper versus lower). Other coatingscan allow for a controlled release of the medication. For example, U.S.Pat. No. 5,458,888, te aches that controlled release dosage forms can beprepared using an external phase of a polyethylene glycol polymer withan average molecular weight of from 3000 to 10000. Additionally, the'888 patent teaches mixing a drug with certain gel forming polymers,allowing for sustained and controlled release in the stomach. Thecombination of the drug with a non-chemically cross-linkedalkyl-substituted cellulose can also provide sustained release in thestomach, according to the method taught in U.S. Pat. No. 5,582,837.

Other techniques allow for delivery of medication to the lower GI tract.Enteric coating materials include cellulose acetate phthalate or aplasticized cellulose acetate phthalate, and are taught in U.S. Pat. No.5,686,106. Furthermore, pH sensitive capsules can allow for delivery tothe more neutral environment of the lower GI tract, as disclosed in U.S.Pat. No. 5,716,648. This can be accomplished by using a coating which isinsoluble in gastric juices of a pH below 4, but soluble in intestinaljuice exhibiting a pH from 4 to 7. For example, polyvinyl acetatephthalate (PVAP) results in release of active ingredients in theduodenum. Hydroxypropyl methylcellulose phthalate (HPMCP) resistssolubility until the environment achieves a pH of at least 5-6. TheHPMCP compounds are available in several forms, some providingprotection for tablets up to pH 6 and 7, respectively, for release intothe colon.

Low solubility formulations can be achieved by mixing the progesteroneor progesterone analog with cyclodextrans according to the methodpresented in U.S. Pat. No. 4,727,064. These can be used as suspensions,or dried into powders for conversion into tablets, capsules, or othersolid dose forms. Certain oils have also been routinely used forsuspensions of water insoluble agents to form liquid preparations or gelcapsules.

Additionally, the progesterone or progesterone analog can beencapsulated in microspheres by a coating of a cross linked coacervateof gelatin and chondroitin sulfate, allowing for time release of thedrug, according to the method taught in U.S. Pat. No. 5,759,582.

Tablets and capsules can be coated with a gum that is broken down byenzymes found in the gut, as disclosed in U.S. Pat. No. 5,656,294.Hydrocolloid gums, obtainable from higher plants, such as guar gum,locust bean gum, gum tragacanth, or karaya gum can be used.

Other strategies for targeted delivery to the colon include thosepresented in Friend et al, Drug Glycosides: potential prodrugs forcolon-specific drug delivery, J. Med. Chem. 28:51-57 (1985); Rubenstein,Microbially controlled drug delivery to the colon, Biopharm & DrugDispos 11:465-475 (1990); Salyers et al, Cellular location of enzymesinvolved in chondroitin sulfate breakdown by Bacteroidesthetaiotaomicron, J. Bacteriol 143:772-780 (1980). Various strategiesfor rectal administration of compounds are described in Marshall et al.,Putting Rectal 5-Aminosalicylic Acid in its Place: The Role in DistalUlcerative Colitis, Am. J. Gastroenterology, 95:1628-1636 (2000).

Very specific delivery can be achieved by using an enteric feeding tubeto deliver” the progesterone or progesterone analog composition directlyto the inflamed section of the gastrointestinal tract, according to themethod presented in U.S. Pat. No. 5,120,306. This technique worksespecially well for delivery to the proximal small bowel. It could alsobe applied to the large bowel, either by using an enteric feeding tubeor by using similar tubing entering the gastrointestinal tract rectally.For psoriasis, the progesterone or progesterone analog could betopically applied to the lesion, injected into the lesion, or injectedinto the body near the lesion.

The progesterone or progesterone analogs used in the methods of thepresent invention may be formulated in a pharmaceutical composition,which may include carriers, thickeners, diluents, buffers,preservatives, surface active agents, tableting agents, liposomes, orlipid formulations, and the like. The pharmaceutical compositions mayalso include one or more active ingredients such as antimicrobialagents, antiinflammatory agents, anesthetics, and the like.

The pharmaceutical composition may be administered in a number of waysdepending on whether local or systemic treatment is desired, and on thearea to be treated. Administration may be topically (including on theskin), rectally (by suppository or enema), intranasally, orally, byinhalation, or parenterally, for example by intravenous drip,subcutaneous, intraperitoneal, intramuscular injection, or injectioninto an area requiring treatment. The activity and metabolism of thecomposition should be used as a guide when determining the route ofadministration.

Formulations for topical, rectal, and intranasal administration mayinclude ointments, lotions, creams, gels, drops, enemas, ointments,suppositories, sprays, liquids, and powders. Conventional pharmaceuticalcarriers, aqueous, powder or oily bases, thickeners, and the like may benecessary or desirable. Compositions for oral administration includepowders or granules, suspensions or solutions in water or nonaqueousmedia, capsules, or tablets. Thickeners, flavorings, diluents,emulsifiers, dispersing aids, tableting agents, or binders may bedesirable. Formulations for parenteral administration may includesterile aqueous solutions optionally containing buffers, liposomes,diluents and other suitable additives.

Dosing is dependent on the severity and responsiveness of the conditionto be treated, with a course of treatment lasting from several days toseveral months or until a cure is effected or a diminution of diseasestate is achieved.

For treatment with an oral composition, in tablet form, for example,dosing is as follows. Optimal dosing schedules and dosing amounts can becalculated based on the severity of the disease and the weight of thepatient according to the general guidelines below. Dosages andfrequencies would be greater for a patient with a more severe diseasestate or a higher weight. Depending on the formulation or whetherlocal/targeted delivery is employed, slightly lower doses would beappropriate.

One oral dosing schedule is to treat a patient suffering frominflammatory conditions, including but not limited to, inflammatorybowel disease (ulcerative colitis, Crohn's disease, and proctitis),other noninfectious, inflammatory conditions of the GI tract(microscopic colitis, allergic eosinophilic gastroenteritis, foodallergies, pill induced esophagitis, celiac disease, recurrent polyps,and hemorrhoids), and psoriasis, with from about 10 mg to about 5 g,alternatively from about 20 mg to about 4 g, alternatively from about 50mg to 3 g, alternatively from about 100 mg to 2 g, alternatively fromabout 500 mg to about 2 g, and alternatively from about 500 mg to about1 g, total daily dose.

For treatment with a topical composition, applied to the skin as acream, gel, or lotion, or administered rectally as a cream, foam, enema,or suppository, dosing is as follows. Optimal dosing schedules anddosing amounts can be calculated based on the severity of the disease,the area of skin to be treated (when applied to the skin) or the volumeof the rectal administration (when applied rectally). Dosages andfrequencies would be greater for a patient with a more severe diseasestate. Dosages, as percent of active ingredient to vehicle, could bereduced when very large areas of the skin are to be treated, and couldbe reduced if a larger volume rectal treatment was used (i.e., a largersuppository, for example).

One topical dosing schedule is to treat a patient suffering frominflammatory conditions, including but not limited to, inflammatorybowel disease (ulcerative colitis, Crohn's disease, and proctitis),other noninfectious, inflammatory conditions of the GI tract(microscopic colitis, allergic eosinophilic gastroenteritis, foodallergies, recurrent polyps, and hemorrhoids), and psoriasis, with fromabout 20 mg to about 4 g, alternatively from about 225 mg to about 1.25g, alternatively from about 550 mg to 750 mg, alternatively about 650mg, total daily dose.

Both oral and topical dosing can occur once a day, every other day,three times a week, or twice a week. It can also occur in divided doses,twice, three, or four times a day. One acceptable dosing schedule isonce a day. Initial treatment can continue for up to 2 weeks for anacute condition, or about 4 weeks to about 16 weeks for a chroniccondition, or alternatively about 8 weeks to about 12 weeks for achronic condition. Longer therapy may also be needed. Patients can betreated for up to six months, or up to one year. Maintenance treatmentcan last up to or longer than one year. Patients can be treated on amaintenance basis or on an as needed basis during a problematic episode,depending on the severity of the patient's condition. Patients can alsobe treated on a rotating treatment basis, where treatment is providedfor a period of time and then the patient is given a drug holiday beforetreatment resumes again. During the drug holiday, patients may receiveno treatment, treatment with another mediation or treatment protocol, ortreatment with a reduced dosage. Additionally, patients could receivetreatment with a higher dose of the composition until a desired reduceddisease state is achieved, and then continued on a lower dose of thecomposition.

Alternatively, the composition could be administered concomitantly withanother treatment for the inflammatory conditions. For example, the drugmay be administered with aminosalicylic acid (ASA) or anotheraminosalicylate, including but not limited to, mesalamine. The seconddrug may be administered in the same composition, or in a differentcomposition. If different compositions are contemplated, the same ordifferent routes of administration could be used depending upon factorsincluding the pharmacokinetics of the compositions, possibleinteractions, and patient convenience/preference.

EXAMPLES

The following examples are presented for illustrative purposes only andare not intended to limit the scope of the invention in any way.

Example 1 Treatment of Mice with Medroxyprogesterone Acetate

The scid (severe combined immunodeficient) C.B.-17 line of mice providean effective model of Inflammatory Bowel Disease. The disease state inthese mice is triggered by the intraperitoneal injection of CD4+ T cellsfrom a normal BALB/C mouse. The induced disease is characterized byintestinal inflammation in the large intestine, leukocytic infiltratesinto the mucosa, submucosa, and mucularis, epithelial cell hyperplasia,loss of mucin-secreting cells, and ulcers with deep fissures, anddiarrhea. In the mouse model, CD4+ T cells and macrophages infiltratethe bowel. The scid mouse is recognized by the art as a model for IBD.Powrie et al., Inhibition of Th1 Responses Prevents Inflammatory BowelDisease in scid Mice Reconstituted with CD45RBhi CD4+ T Cells, Immunity1:553-562 (1994).

500,000 to 1×106 T cells derived from the lymph nodes of normal BALB/Cmice were injected intraperitoneally into scid mice 6 weeks prior tosacrifice. 2 days before lymphocyte administration, treatment of thescid mice began with buffer control, medroxyprogesterone acetate, or17-hydroxyprogesterone. The treatment mice (5 in each group) received 25mg/kg of drug orally each day until sacrifice. Two BALB/C mice served asan additional negative control for the mouse model, and did not receivethe intraperitoneal injections.

After sacrifice, lamina propria (bowel wall) lymphocytes were isolatedfrom each animal. The total number of lymphocytes, number of CD4+lymphocytes, and the percent of CD4+ lymphocytes was determined. CD4+lymphocytes were identified by using a first antibody directed to CD4,and a second antibody directed to the first antibody. The secondantibody was tagged with fluorescein, which lights up as green in a flowcytometer, identifying which lymphocytes are the CD4+ form. The resultsare shown in Table 1. Lymphocyte infiltration into the bowel is apredictor of the progress of the disease because lymphocytes areinvolved in the inflammatory response leading to damage of the bowelwall.

The results show that medroxyprogesterone acetate is effective indecreasing lymphocyte infiltration into the bowel, compared to thebuffer control and 17-hydroxyprogesterone. 17-hydroxyprogesterone didnot work in treating the mice. This may be due in part to the lesserclassic sex organ progestational activity of 17-hydroxyprogesterone,which is believed to be one mode of action of the progesterone analogsin treating IBD. The BALB/C mice show the normal baseline level oflymphocytes in the bowel and the buffer control shows the state of thedisease model without any treatment. Table 1 shows the effect oftreatment on lymphocytes infiltration in the large bowel lamina propria.TABLE 1 Effect of treatment on lymphocytes infiltrating the large bowellamina propria CD4+ CD4+ as a Total Lymphocytes percent of totalLymphocytes Treatment (1 × 106) Lymphocytes (1 × 106) Buffer Control19.3 89 23 22 88 25 3.2 88 3.6 22 69 31.8 32 87 36.9 Average 19.7 84.224.1 Medroxyprogesterone 1.6 81 2 Acetate 4.1 87 4.8 1.3 65 2 3.0 83 3.69.2 91 10.2 Average 3.8 81.4 4.5 17- 8.9 89 10 hydroxyprogesterone 1.681 2 15 93 16.5 23 91 25.2 Average 16.3 88.0 18.4 BALB/C mice 2.2 1911.6 0.8 18 5.4 Average 1.5 18.5 8.5

Example 2 Effect of Medroxyprogesterone Acetate on Macrophage TNF-αRelease

The spleens of six of the mice from Example 1 were removed after theanimals were sacrificed. Macrophages were isolated from the spleen ofthe medroxyprogesterone acetate or buffer control treated mice. TNF-αrelease from these macrophages was measured by ELISA followingstimulation with either (1) rat anti-mouse macrophage Fc receptorantibody 2.4G2 and F(ab′)₂ IgG goat anti-rat antibody, or (2) phorbolmyristate acetate (“PMA”), a phorbol ester. The effect ofmedroxyprogesterone acetate on TNF-α release is illustrated in Table 2.TABLE 2 Effect of Medroxyprogesterone Acetate on TNF-α Release TNF-αTNF-α Repeat Measurement Measurement Mouse Treatment Stimulation (pg/ml)(pg/ml) 1 Buffer 2.4G2 and F(ab′)₂ 2575 2053 2 IgG anti-rat 1873 1112 3MPA 1843 0 4 2314 1026 5 Buffer 2.4G2 and F(ab′)₂ 56220 936 6 MPA IgGanti-rat for 1^(st) 27563 0 Measurement and PMA for Repeat Measurement

Thus, these results suggest that medroxyprogesterone acetate may beinhibiting TNF-α release from macrophages, either by inhibiting itsproduction, release, or down-regulating Fc receptors on the macrophages.Macrophages are involved in inflammatory processes, and infiltrate thebowel wall causing damage in inflammatory bowel diseases.

Example 3 Effect of Medroxyprogesterone Acetate on Macrophage IL-6Release

The spleens of four of the mice from Example 1 were removed after theanimals were sacrificed. Macrophages were isolated from the spleen ofthe medroxyprogesterone acetate or buffer control treated mice. IL-6release from these macrophages was measured by ELISA followingstimulation with rat anti-mouse macrophage Fc receptor antibody 2.4G2and F(ab′)₂ IgG goat anti-rat antibody. The effect ofmedroxyprogesterone acetate on IL-6 release is illustrated in Table 3.TABLE 3 Effect of Medroxyprogesterone Acetate on IL-6 Release MouseTreatment Stimulation IL-6 Measurement 1 Buffer 2.4G2 and F(ab′)₂323,406 2 IgG anti-rat 310,750 3 MPA 298,940 4 266,557

Thus, these results suggest that medroxyprogesterone acetate may beinhibiting IL-6 release from macrophages, either by inhibiting itsproduction, release, or down-regulating Fc receptors on the macrophages.Macrophages are involved in inflammatory processes, and infiltrate thebowel wall causing damage in inflammatory bowel diseases.

Example 4 Treatment of Patients with Ulcerative Colitis

Patients with mild to moderate ulcerative colitis were evaluated fortheir response to treatment with medroxyprogesterone acetate. Patientsin the treatment group (8 patients) received a loading dose of 1 gram ofmedroxyprogesterone acetate every 6 hours for 8 doses. These patientswere then given 500 mg of medroxyprogesterone every 12 hours for 8weeks.

Disease improvement was measured using the Disease Activity Index (DAI).The DAI is a total score for stool frequency, blood in the stool, theinvestigator's global assessment (IGA), and the physician's evaluationof the appearance of mucosa during flexible sigmoidoscopy of the colon.Patients showed improvement if they had a reduction of one or more unitsin the DAI score at the end of the study, when compared to baseline.Table 4 shows patient improvement with treatment. TABLE 4 PatientImprovement with Treatment for Ulcerative Colitis Patient NumberImprovement 1 Yes 2 No 3 Yes 4 No 5 Yes 6 Yes 7 Yes 8 No

Thus, medroxyprogesterone acetate represents a good treatment forulcerative colitis. Five out of eight patients showed improvement withtreatment (8 weeks). Of the 3 patients who did not respond at the end ofthe 8 week study, 2 patients demonstrated a reduction in symptoms andcomplaints during initial treatment.

Example 5 Treatment of Patients with Crohn's Disease

Patients with mild to moderate Crohn's disease were evaluated for theirresponse to treatment with medroxyprogesterone acetate. Patients in thetreatment group (12 patients) received a loading dose of 1 gram ofmedroxyprogesterone acetate every 6 hours for 8 doses. These patientswere then given 500 mg of medroxyprogesterone every 12 hours for 8weeks.

Disease improvement was measured using the Crohn's Disease ActivityIndex (CDAI). The CDAI score for a patient was calculated by multiplyingthe numerical value for each variable by the multiplication factorindicated for that variable, and totaling all of the resultant values,as shown in Table 5. A score below 150 indicated remission and a scoreabove 450 indicated severe disease. In order to enter the study,patients were required to have a total CDAI score of 200 to 400 atbaseline. TABLE 5 Determination of CDAI Score Multiplication VariableFactor Number of liquid or soft stools (over 7 days) 2 Abdominal pain(sum of scores over 7 days) 5 0 = none, 1 or 2 = intermediate, 3 =severe General well-being (sum of scores over 7 days) 7 0 = good to 4 =terrible Number of complications (on day of 20 assessment except forfever) arthalgias or arthritis iritis or uveitis erythema nodosum,pyoderma gangrenosum, or aphthous stomatits anal fissure, fistula, orabscess other fistula fever (>37.8° C., over 7 days) Use of opiates fordiarrhea 30 0 = no, 1 = yes Abdominal Mass (on day of assessment) 10 0 =none, 2 = questionable, 5 = definite 47 minus hematocrit (men), 42 minus6 hematocrit (women) (day of assessment) Percentage deviation above orbelow standard 1 weight (on day of assessment) according to theMetropolitan Life Insurance Height and Weight Tables for Men and forWomen

Disease remission was defined as a CDAI score of 150 or below. Diseaseresponse was defined as either a decrease of 70 or greater in the CDAIor disease remission. Table 6 shows patient response to treatment. TABLE6 Patient Response to Treatment for Crohn's Disease Number of PatientType Patients Remissions Responders Completers 10 7 8 Ongoing 1 — — Dropout 1 — —

Of the patients treated, eight out of ten responded to therapy (8weeks). One patient dropped out for a minor adverse event (fatigue) andhad no efficacy data. The remaining patient is still continuing on thestudy. Thus, medroxyprogesterone acetate represents a good treatment forCrohn's disease.

Other embodiments of the invention will be apparent to those skilled inthe art from consideration of the specification and practice of theinvention disclosed herein. It is intended that the specification andexamples be considered as exemplary only, with a true scope and spiritof the invention being indicated by the following claims. All of thedocuments cited within this application are hereby incorporated byreference.

1. A method of treating a patient suffering from at least one of thefollowing inflammatory conditions: inflammatory bowel disease(ulcerative colitis, Crohn's disease, and proctitis), microscopiccolitis, allergic eosinophilic gastroenteritis, food allergies, pillinduced esophagitis, celiac disease, recurrent polyps, hemorrhoids, andpsoriasis, wherein a progesterone or progesterone analog is selected andadministered to the patient.
 2. The method of claim 1, wherein theprogesterone analog has high progestational activity.
 3. The method ofclaim 1, wherein the progesterone analog is medroxyprogesterone acetate.4. The method of claim 3, wherein the patient is treated withmedroxyprogesterone acetate once a day.
 5. The method of claim 3,wherein the patient is treated with from about 500 mg to about 2 gramsof medroxyprogesterone acetate daily.
 6. The method of claim 1, whereinthe progesterone analog is administered orally.
 7. The method of claim1, wherein the patient is suffering from at least one of the followinginflammatory conditions: inflammatory bowel disease (ulcerative colitis,Crohn's disease, and proctitis), microscopic colitis, allergiceosinophilic gastroenteritis, food allergies, recurrent polyps, andhemorrhoids.
 8. The method of claim 7, wherein the progesterone analogis formulated in an enteric coated tablet to allow for targeted deliveryto the affected portion of the bowel.
 9. The method of claim 7, whereinthe progesterone analog is administered rectally using a compositionchosen from an enema, a suppository, a foam, a cream, a gel, anointment, and a suspension.
 10. The method of claim 1, wherein thepatient is suffering from psoriasis.
 11. The method of claim 10, whereinthe progesterone analog is applied to the skin, injected into at leastone psoriasis lesion, or injected into the body near at least onepsoriasis lesion.